Search

PURPOSE: Brain metastasis is common in lung cancer, and treatment of brain metastasis can lead to significant morbidity. Although early detection of brain metastasis may improve outcomes, there are no prediction models to identify high-risk patients for brain magnetic resonance imaging (MRI) surveillance. Our goal is to develop a machine learning–based clinicogenomic prediction model to estimate patient-level brain metastasis risk. METHODS: A penalized regression competing risk model was developed using 330 patients diagnosed with lung cancer between January 2014 and June 2019 and followed through June 2021 at Stanford HealthCare. The main outcome was time from the diagnosis of distant metastatic disease to the development of brain metastasis, death, or censoring. RESULTS: Among the 330 patients, 84 (25%) developed brain metastasis over 627 person-years, with a 1-year cumulative brain metastasis incidence of 10.2% (95% CI, 6.8 to 13.6). Features selected for model inclusion were histology, cancer stage, age at diagnosis, primary site, and RB1 and ALK alterations. The prediction model yielded high discrimination (area under the curve 0.75). When the cohort was stratified by risk using a 1-year risk threshold of > 14.2% (85th percentile), the high-risk group had increased 1-year cumulative incidence of brain metastasis versus the low-risk group (30.8% v 6.1%, P <.01). Of 48 high-risk patients, 24 developed brain metastasis, and of these, 12 patients had brain metastasis detected more than 7 months after last brain MRI. Patients who missed this 7-month window had larger brain metastases (58% v 33% largest diameter > 10 mm; odds ratio, 2.80, CI, 0.51 to 13) versus those who had MRIs more frequently. CONCLUSION: The proposed model can identify high-risk patients, who may benefit from more intensive brain MRI surveillance to reduce morbidity of subsequent treatment through early detection. [ABSTRACT FROM AUTHOR]

Background: GBM astrocytes may adopt fetal astrocyte transcriptomic signatures involved in brain development and migration programs to facilitate diffuse tumor infiltration. Our previous data show that ETS variant 6 (ETV6) is highly expressed in human GBM and fetal astrocytes compared to normal mature astrocytes. We hypothesized that ETV6 played a role in GBM tumor progression. Methods: Expression of ETV6 was first examined in two American and three Chinese tissue microarrays. The correlation between ETV6 staining intensity and patient survival was calculated, followed by validation using public databases—TCGA and REMBRANDT. The effect of ETV6 knockdown on glioma cell proliferation (EdU), viability (AnnexinV labeling), clonogenic growth (colony formation), and migration/invasion (transwell assays) in GBM cells was tested. RNA sequencing and Western blot were performed to elucidate the underlying molecular mechanisms. Results: ETV6 was highly expressed in GBM and associated with an unfavorable prognosis. ETV6 silencing in glioma cells led to increased apoptosis or decreased proliferation, clonogenicity, migration, and invasion. RNA-Seq-based gene expression and pathway analyses revealed that ETV6 knockdown in U251 cells led to the upregulation of genes involved in extracellular matrix organization, NF-κB signaling, TNF-mediated signaling, and the downregulation of genes in the regulation of cell motility, cell proliferation, PI3K-AKT signaling, and the Ras pathway. The downregulation of the PI3K-AKT and Ras-MAPK pathways were further validated by immunoblotting. Conclusion: Our findings suggested that ETV6 was highly expressed in GBM and its high expression correlated with poor survival. ETV6 silencing decreased an aggressive in vitro phenotype probably via the PI3K-AKT and Ras-MAPK pathways. The study encourages further investigation of ETV6 as a potential therapeutic target of GBM. [ABSTRACT FROM AUTHOR]

Introduction: The coronavirus disease 2019 (COVID-19) heralded an unprecedented increase in telemedicine utilization. Our objective was to assess patient satisfaction with telemedicine during the COVID-19 era. Methods: Telemedicine visit data were gathered from Stanford Health Care (Stanford) and the Hospital for Special Surgery (HSS). Patient satisfaction data from HSS were captured from a Press-Ganey questionnaire between April 19, 2020, and December 12, 2020, whereas Stanford data were taken from a novel survey instrument that was distributed to all patients between June 22, 2020, and November 1, 2020. Participants: There were 60,550 telemedicine visits at Stanford, each linked with a postvisit survey. At HSS, there were 66,349 total telemedicine visits with 7,348 randomly linked with a postvisit survey. Main Outcomes and Measures: Two measures of patient satisfaction were used for this study: (1) a patient's "overall visit score" and (2) whether the patient indicated the highest possible "likelihood to recommend" (LTR) score (LTR top box score). Results: The LTR top box percentage at Stanford increased from 69.6% to 74.0% (p = 0.0002), and HSS showed no significant change (p = 0.7067). In the multivariable model, the use of a cell phone (adjusted odds ratio [aOR]: 1.18; 95% confidence interval [CI]: 1.12–1.23) and tablet (aOR: 1.15; 95% CI: 1.07–1.23) was associated with higher overall scores, whereas visits with interrupted connections (aOR: 0.49; 95% CI: 0.42–0.57) or help required to connect (aOR: 0.49; 95% CI: 0.42–0.56) predicted lower patient satisfaction. Conclusions: We present the largest published description of patient satisfaction with telemedicine, and we identify important telemedicine-specific factors that predict increased overall visit score. These include the use of cell phones or tablets, phone reminders, and connecting before the visit was scheduled to begin. Visits with poor connectivity, extended wait times, or difficulty being seen, examined, or understood by the provider were linked with reduced odds of high scores. Our results suggest that attention to connectivity and audio/visual definition will help optimize patient satisfaction with future telemedicine encounters. [ABSTRACT FROM AUTHOR]

While neurotrophic tropomyosin receptor kinase (NTRK) fusions represent rare oncogenic drivers (<1% of solid cancers), the recent approval of NTRK inhibitors (larotrectinib and entrectinib) led to dramatic responses in patients with NTRK fusion+ tumors. Both drugs have phase I data, demonstrating efficacy in the central nervous system (CNS), including both primary brain tumors and brain metastases. We present a 29-year-old woman who was diagnosed with NTRK3-SPECC1L fusion+ undifferentiated uterine sarcoma and underwent resection, chemotherapy, and radiotherapy. Two years later, lung metastases were discovered. She was started on larotrectinib with complete response. She remained stable on larotrectinib until she presented with altered mental status and seizures. MRI demonstrated leptomeningeal enhancement, but because leptomeningeal progression from sarcoma is exceedingly rare and her symptoms improved dramatically with antiepileptics, these findings were initially attributed to seizures. After 2 unrevealing lumbar punctures and stable systemic imaging, a brain biopsy demonstrated metastatic sarcoma, still showing NTRK positivity. She underwent whole brain radiotherapy and was switched to entrectinib, but had clinical progression 1 month later and transitioned to hospice. This case demonstrates the efficacy of NTRK inhibitors in rare and aggressive cancer but highlights that these patients can develop isolated CNS progression even in the setting of CNS-penetrant drugs. CNS progression can occur if there is incomplete CNS drug penetration, discordance in molecular profiles between CNS and systemic disease, or acquired NTRK inhibitor resistance. In this case, CNS disease maintained the NTRK fusion status, but either inadequate CNS penetration or development of a resistance gene may explain the isolated CNS progression. [ABSTRACT FROM AUTHOR]

Introduction: Gliosarcomas are clinically aggressive tumors, histologically distinct from glioblastoma. Data regarding the impact of extent of resection and post-operative adjuvant therapy on gliosarcoma outcomes are limited. Methods: Patients with histologically confirmed gliosarcoma diagnosed between 1999 and 2019 were identified. Clinical, molecular, and radiographic data were assembled based on historical records. Comparisons of categorical variables used Pearson's Chi-square and Fisher's exact test while continuous values were compared using the Wilcoxon signed-rank test. Survival comparisons were assessed using Kaplan-Meier statistics and Cox regressions. Results: Seventy-one gliosarcoma patients were identified. Secondary gliosarcoma was not associated with worse survival when compared to recurrent primary gliosarcoma (median survival 9.8 [3.8 to 21.0] months vs. 7.6 [1.0 to 35.7], p = 0.7493). On multivariable analysis, receipt of temozolomide (HR = 0.02, 95% CI 0.001–0.21) and achievement of gross total resection (GTR; HR = 0.13, 95% CI 0.02–0.77) were independently prognostic for improved progression-free survival (PFS) while only receipt of temozolomide was independently associated with extended overall survival (OS) (HR = 0.03, 95% CI 0.001–0.89). In patients receiving surgical resection followed by radiotherapy and concomitant temozolomide, achievement of GTR was significantly associated with improved PFS (median 32.97 [7.1–79.6] months vs. 5.45 [1.8–26.3], p = 0.0092) and OS (median 56.73 months [7.8–104.5] vs. 14.83 [3.8 to 29.1], p = 0.0252). Conclusion: Multimodal therapy is associated with improved survival in gliosarcoma. Even in patients receiving aggressive post-operative multimodal management, total surgical removal of macroscopic disease remains important for optimal outcomes. [ABSTRACT FROM AUTHOR]

Objective/Background: We report efficacy and toxicity outcomes with stereotactic radiosurgery (SRS) for intracranial and spinal ependymoma. Methods: We analyzed adult and pediatric patients with newly diagnosed or recurrent intracranial or spinal ependymoma lesions treated with SRS at our institution. Following SRS, local failure (LF) was defined as failure within or adjacent to the SRS target volume, while distant failure (DF) was defined as failure outside of the SRS target volume. Time to LF and DF was analyzed using competing risk analysis with death as a competing risk.Overall survival (OS) was calculated from the date of first SRS to the date of death or censored at the date of last follow-up using the Kaplan-Meier method. Results: Twenty-one patients underwent SRS to 40 intracranial (n = 30) or spinal (n = 10) ependymoma lesions between 2007 and 2018, most commonly with 18 or 20 Gy in 1 fraction. Median follow-up for all patients after first SRS treatment was 54 months (range 2–157). The 1-year, 2-year, and 5-year rates of survival among patients with initial intracranial ependymoma were 86, 74, and 52%, respectively. The 2-year cumulative incidences of LF and DF after SRS among intracranial ependymoma patients were 25% (95% CI 11–43) and 42% (95% CI 22–60), respectively. No spinal ependymoma patient experienced LF, DF, or death within 2 years of SRS. Three patients had adverse radiation effects. Conclusions: SRS is a viable treatment option for intracranial and spinal ependymoma with excellent local control and acceptable toxicity. [ABSTRACT FROM AUTHOR]

The specific function of microglia, the tissue resident macrophages of the brain and spinal cord, has been difficult to ascertain because of a lack of tools to distinguish microglia from other immune cells, thereby limiting specific immunostaining, purification, and manipulation. Because of their unique developmental origins and predicted functions, the distinction of microglia from other myeloid cells is critically important for understanding brain development and disease; better tools would greatly facilitate studies ofmicroglia function in the developing, adult, and injured CNS. Here, we identify transmembrane protein 119 (Tmem119), a cell-surface protein of unknown function, as a highly expressed microglia-specific marker in both mouse and human. We developed monoclonal antibodies to its intracellular and extracellular domains that enable the immuno-staining of microglia in histological sections in healthy and diseased brains, as well as isolation of pure nonactivated microglia by FACS. Using our antibodies, we provide, to our knowledge, the first RNAseq profiles of highly pure mouse microglia during development and after an immune challenge. We used these to demonstrate that mouse microglia mature by the second postnatal week and to predict novel microglial functions. Together, we anticipate these resources will be valuable for the future study and understanding of microglia in health and disease. [ABSTRACT FROM AUTHOR]

The human brain is a tissue of vast complexity in terms of the cell types it comprises. Conventional approaches to classifying cell types in the human brain at single cell resolution have been limited to exploring relatively few markers and therefore have provided a limited molecular characterization of any given cell type. We used single cell RNA sequencing on 466 cells to capture the cellular complexity of the adult and fetal human brain at a whole transcriptome level. Healthy adult temporal lobe tissue was obtained during surgical procedures where otherwise normal tissue was removed to gain access to deeper hippocampal pathology in patients with medical refractory seizures. We were able to classify individual cells into all of the major neuronal, glial, and vascular cell types in the brain. We were able to divide neurons into individual communities and show that these communities preserve the categorization of interneuron subtypes that is typically observed with the use of classic interneuron markers. We then used single cell RNA sequencing on fetal human cortical neurons to identify genes that are differentially expressed between fetal and adult neurons and those genes that display an expression gradient that reflects the transition between replicating and quiescent fetal neuronal populations. Finally, we observed the expression of major histocompatibility complex type I genes in a subset of adult neurons, but not fetal neurons. The work presented here demonstrates the applicability of single cell RNA sequencing on the study of the adult human brain and constitutes a first step toward a comprehensive cellular atlas of the human brain. [ABSTRACT FROM AUTHOR]

Central nervous system tumors carry grave clinical prognoses due to limited effectiveness of surgical resection, radiation, and chemotherapy. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. We demonstrate that mouse cerebellar medulloblastoma (MB) can be targeted and illuminated with a fluorescent, engineered cystine knot (knottin) peptide that binds with high affinity to αvβ3, αvβ5, and α5β1 integrin receptors. This integrin-binding knottin peptide, denoted EETI 2.5F, was evaluated as a molecular imaging probe in both orthotopic and genetic models of MB. Following tail vein injection, fluorescence arising from dye-conjugated EETI 2.5F was localized to the tumor compared with the normal surrounding brain tissue, as measured by optical imaging. The imaging signal intensity correlated with tumor volume. Due to its unique ability to bind to α5β1 integrin, EETI 2.5F showed superior in vivo and ex vivo brain tumor imaging contrast compared with other engineered integrin-binding knottin peptides and with c(RGDfK), a well-studied integrin-binding peptidomimetic. Next, EETI 2.5F was fused to an antibody fragment crystallizable (Fc) domain (EETI 2.5F-Fc) to determine if a larger integrin-binding protein could also target intracranial brain tumors. EETI 2.5F-Fc, conjugated to a fluorescent dye, illuminated MB following i.v. injection and was able to distribute throughout the tumor parenchyma. In contrast, brain tumor imaging signals were not detected in mice injected with EETI 2.5F proteins containing a scrambled integrin-binding sequence, demonstrating the importance of target specificity. These results highlight the potential of using EETI 2.5F and EETI 2.5-Fc as targeted molecular probes for brain tumor imaging. [ABSTRACT FROM AUTHOR]

Background/Aims: To review the pathological distribution of pediatric primary skull tumors, and to determine the diagnostic value of lesion location, patient age and lesion size. Methods: A retrospective chart review identified 51 consecutive pediatric patients with 54 primary skull tumors, treated between 2005 and 2010. Results: The most common diagnoses were dermoid cysts (n = 34) and fibrous dysplasia (n = 5). While dermoid tumors could reside anywhere (sensitivity = 0.41), a midline lesion had a specificity of 0.9 and a positive predictive value of 0.88. All of the fibrous dysplasia lesions were laterally placed, with a negative predictive value (NPV) of 1. Patient age < or >5 years had a high sensitivity and NPV for dermoid cysts and fibrous dysplasia, respectively. Size appeared to be sensitive (0.91, 0.8), but not specific (0.6, 0.78), with good NPV (0.8, 0.97) when considering dermoid cysts (≤2 cm) or fibrous dysplasia (>2 cm), respectively.Conclusion:Dermoid cysts followed by fibrous dysplasia are the most common primary skull tumors. Lesion location, patient age and lesion size give important clues as to the diagnosis. For the majority of cases, a clinical diagnosis based on CT is sufficient for presurgical evaluation. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In 2016, the World Health Organization revised its guidelines to retain only gemistocytic astrocytoma (GemA) as a distinct variant of diffuse astrocytoma (DA). In the past, grade II GemAs were linked with a worse prognosis than DA. However, it is unclear how consistently the tumor subtype has been diagnosed over time. We used more recent data to compare outcomes between grade II GemA and DA. Patients with grade II DA and GemA were extracted from the Surveillance, Epidemiology, and End Results database between 1973 and 2016. Kaplan-Meier curves estimated survival differences across different eras, with a focus on patients diagnosed between 2000 and 2016, and propensity score matching was used to balance baseline characteristics between DA and GemA cohorts. Of 2467 patients with grade II astrocytoma diagnosed between 2000 and 2016, 132 (5.35%) had GemA, and 2335 (94.65%) had DA. At baseline, marked demographic and treatment differences were noted between tumor subtypes, including age at diagnosis and female sex. GemA patients did not have worse survival compared with DA patients at baseline (P = 0.349) or after propensity score matching (P = 0.497). Multivariate Cox models found that surgical extent of resection was associated with a survival benefit for DA patients, and both DA and GemA patients >65 years old had dramatically inferior survival. Our data suggest that the impact of GemA versus DA histopathology depends more on the decade of queried data rather than patient-specific demographics. Using more recent longitudinal data, we found that grade II GemA and DA tumors did not have significant differences in survival. These data may prove useful for clinicians counseling patients with grade II GemA. [ABSTRACT FROM AUTHOR]

In the present study, we used a validated socioeconomic status (SES) index and population-based registry to identify and quantify the impact of SES on access to treatment and overall survival for patients diagnosed with synchronous brain metastases. The Surveillance, Epidemiology, and End Results database was used to extract all patients between 2010 and 2016 with brain metastases at initial presentation. SES was stratified into tertiles and quintiles using the validated Yost index. Multivariable logistic regressions were used to evaluate the impact of demographic, tumor, and socioeconomic covariates on receipt of radiotherapy and chemotherapy. Kaplan-Meier curves were used to estimate survival. Between 2010 and 2016, 35,595 patients presented with brain metastases at the time of primary cancer diagnosis. Most patients received radiation and/or chemotherapy as part of the initial course of their treatment; 71.6% (n = 25,484) were irradiated while 54.4% (n = 19,371) received chemotherapy and 44.9% (n = 15,984) received chemoradiation. Patients in the highest Yost tertile and quintile experienced longer overall survival (P < 0.001). Additionally, multivariable logistic regression revealed that the lowest Yost quintile was significantly less likely to receive either radiation (adjusted OR: 0.82; 95% confidence interval: 0.75–0.89; P < 0.001) or chemotherapy (adjusted OR: 0.62; 95% confidence interval: 0.58–0.67; P < 0.001). In a large, population-based analysis of brain metastasis patients, we found significant differences in treatment access and mild survival differences along socioeconomic strata. More specifically, patients in lower SES tiers suffered worse outcomes and received radiation and chemotherapy less frequently than patients in higher tiers, even after accounting for other tumor- and demographic-related information. [ABSTRACT FROM AUTHOR]

Few prognostic markers are available for patients with non-small-cell lung cancer (NSCLC) undergoing neurosurgical resection of symptomatic brain metastases. We investigated whether tumor mutation status (EGFR , KRAS, ALK, ROS1, and BRAF) and treatment history were associated with survival after neurosurgery. We reviewed the electronic health records of 104 patients with NSCLC with genomic profiling who underwent neurosurgical resection for symptomatic brain metastases at an academic institution between January 2000 and January 2018. We used multivariate Cox proportional hazards regression models to evaluate the association between overall survival (OS) after neurosurgery and clinicopathologic factors, including mutation status. Mean age of patients in this study was 61 (±12) years, and 44% were men. The median OS after neurosurgery was 24 months (95% confidence interval, 18–34 months). Our multivariate analysis showed that the presence of an EGFR mutation in the tumor was significantly associated with improved OS (hazard ratio [HR], 0.214; P = 0.029), independent of tyrosine kinase inhibitor use. Presence of KRAS , ALK , ROS1 , and BRAF alterations was not associated with survival (all P > 0.05). Conversely, older age (HR, 1.039; P = 0.029), a history of multiple brain irradiation procedures (HR, 9.197; P < 0.001), and presence of extracranial metastasis (HR, 2.556; P = 0.016) resulted in increased risk of mortality. Patients requiring surgical resection of an epidermal growth factor receptor–mutated NSCLC brain metastasis had an associated improved survival compared with patients without this mutation, independent of tyrosine kinase inhibitor use. Decreased survival was associated with older age, multiple previous brain radiation therapies, and extracranial metastasis. [ABSTRACT FROM AUTHOR]

Summary Microglia, the brain’s resident macrophages, are dynamic CNS custodians with surprising origins in the extra-embryonic yolk sac. The consequences of their distinct ontogeny are unknown but critical to understanding and treating brain diseases. We created a brain macrophage transplantation system to disentangle how environment and ontogeny specify microglial identity. We find that donor cells extensively engraft in the CNS of microglia-deficient mice, and even after exposure to a cell culture environment, microglia fully regain their identity when returned to the CNS. Though transplanted macrophages from multiple tissues can express microglial genes in the brain, only those of yolk-sac origin fully attain microglial identity. Transplanted macrophages of inappropriate origin, including primary human cells in a humanized host, express disease-associated genes and specific ontogeny markers. Through brain macrophage transplantation, we discover new principles of microglial identity that have broad applications to the study of disease and development of myeloid cell therapies. [ABSTRACT FROM AUTHOR]

A benchmark of success for the neurosurgeon-scientist includes obtaining individual research funding from the National Institutes of Health. Successful roadmaps to this goal highlight diversity, individual commitment and resiliency, innovative research goals, intentional mentoring, protected research time, and financial support. We must equip neurosurgery residents to surmount obstacles such as long periods of training, gaps in research productivity, and limited protected time for research to ensure successful transition to independent research careers. Strong individual, departmental, and national commitment to scientific development of a diverse cohort of residents and junior faculty will increase the number and diversity of National Institutes of Health-funded neurosurgeon-scientists., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

A benchmark of success for the neurosurgeon-scientist includes obtaining individual research funding from the National Institutes of Health. Successful roadmaps to this goal highlight individual commitment and resiliency, innovative research goals, intentional mentoring, protected research time, and financial support. Neurosurgery residents must carefully plan their training career to surmount obstacles such as long clinical training period, gaps in research productivity during clinical training, and limited protected time for research to ensure successful transition to independent research careers. To maximize potential for success as a neurosurgeon-scientist, individuals should have strong research experience on entering residency, choose residency programs that enthusiastically commit to research success among its residents, choose research mentors who will guide them expertly toward a research career, and become well-prepared to apply for research funding during residency. Moreover, individuals who wish to become leaders as neurosurgeon-researchers should seek environments that provide exposure to the widest range of experiences, perspectives, and thinking about medical and research problems., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)